DESCRIPTION (Verbatim from the application): The long-term objective of this application is to identify whether oxidative stress is responsible for the induction of the phenotypic characteristics of the aging heart and whether interference with the aging phenotype positively modifies the detrimental effects of coronary artery disease, the most common cause of death in the elderly. These hypotheses will be tested in a mouse model in which targeted mutation of the p66shc gene enhances the resistance of cells to reactive 02 and prolongs maximum lifespan by 30 percent. This constitutes the first demonstration that a gene can influence the duration of life in mammals, offering the unique opportunity to compare hearts from animals of the same age, but with different lifespans. On this basis, the currently unknown aging phenotype of the heart may be, at least in part, recognized. Coronary artery narrowing (CAN) mimics coronary atherosclerosis, increases the generation of reactive oxygen species (ROS) and results in scattered cell death across the ventricular wall. Ablation of p66shc may improve the ability of the heart to sustain ischemic injury, attenuating the impact of ROS production on cell viability and function. High levels of ROS promote cell necrosis and lower levels trigger apoptosis. The activation of death signals is largely dependent on the antioxidant defense mechanisms of cardiac cells. Because mitochondria comprise more than one third of the myocyte cytoplasm, large amounts of ROS may be generated in this cell population, but its antioxidant enzymes may be much more effective than in other cardiac cell types. Additionally, cells interact with each other in situ, making it impossible to predict whether oxidative stress will damage first myocytes, endothelial cells, smooth muscle cells or fibroblasts. ROS formation in vivo may be initially insufficient to induce cell death but sufficient to alter cytosolic Ca2+ and pHi These defects may change the mechanical behavior of ventricular myocytes and arterial smooth muscle cells, as well as the metabolic state and function of endothelial cells and fibroblasts. Cell death and a structural aging phenotype may predominate with the progression of life. However, abnormalities in cell and muscle function and a physiologic phenotype may precede, accompany or follow the structural phenotype. By measuring multiple parameters at the organ, tissue and cellular levels with aging alone or in combination with CAN, in wild-type and p66shc-/- mice, in the presence and absence of treatments potentiating or decreasing 02 toxicity, the aging phenotype of the heart may ultimately be characterized.